Mechanisms and therapies of B7x and B7-H3 in T1D T cell co-stimulation and co-inhibition generated by the B7 family and their receptor CD28 family have key roles in regulating T lymphocyte activation and tolerance. Therefore these pathways are very attractive therapeutic targets. In addition to the long-standing pathway of B7-1/B7-2/CD28/CTLA-4, we and others have discovered several additional members of the B7/CD28 families over the last several years, including B7h/ICOS, PD- L1(B7-H1)/PD-L2(B7-DC)/PD-1, B7-H3/receptor(s), B7x(B7-H4 or B7S1)/receptor(s), and HHLA2/TMIGD2/receptors. Type 1 diabetes (T1D) is an autoimmune disease characterized by infiltration of lymphocytes into the islets of the pancreas and then breakdown of glucose homeostasis as a result of destruction of insulin-producing ? cells by T cells. The incidence of T1D has risen steadily. Little is known about the roles of B7x and B7-H3 in the regulation of T cell function in peripheral non-lymphoid organs such as the pancreas where T1D occurs. Based on our recently published work and our exciting preliminary data, we have hypothesized in this proposal that B7x and B7-H3 are coinhibitors of effector T cells in T1D and are new therapeutic targets. This hypothesis will be tested by pursuing three specific aims: 1) Specific Aim 1: Dissect the mechanisms by which B7x inhibits T1D development; 2) Specific Aim 2: Determine the physiologic roles of B7-H3 in T1D; and 3) Specific Aim 3: Assess the therapeutic efficacy in T1D by targeting the B7x and B7-H3 pathways. We have generated a number of novel tools and have assembled a multi-disciplinary team with complementary skill sets, which provides us with unique opportunities to address challenges and achieve our goals.